This is an application for a Mentored Patient-Oriented Research Career Development Award (K23) entitled "Functional neuroimaging of cue-induced heroin craving". The candidate's previous training and experience was in clinical psychiatry and nuclear medicine. Through this proposal, the candidate seeks to gain advanced training in: (1) functional magnetic resonance imaging (fMRI) and cognitive neuroscience methodology relevant to addiction research; (2) clinical research design and analysis, with a special emphasis on advanced statistical analysis of fMRI data and power analyses. The research project that is designed to complement this training program will use fMRI and experimental psychology methods to investigate the regional cerebral blood flow (CBF) changes during drug craving induced by heroin-related cues to identify the brain networks mediating opiate craving. Studies by the investigators at candidates' laboratory and institution laid out the principles of drug-related conditioned response in opiate-dependent patients and of Arterial Spin Labeling (perfusion) fMRI. Perfusion fMRI is particularly well suited for imaging of relatively prolonged states (e.g. cue-induced craving) and protocols involving repeated within-subject experiments separated by days or weeks, such as the study of chronic medication effects. The candidate has extensive experience in the management of opiate dependence. An on-going pilot study by the candidate suggests an association between activation of the ventral tegmental area and heroin craving induced by opiate-related cues in methadone-maintained patients. The proposed project will expand and elaborate upon the previous findings and technological developments. Specific Aim 1 is to use fMRI to characterize the pattern of CBF response to cue-induced heroin craving and determine the specificity of this pattern in opiate-dependent subjects, building on the pilot data obtained by the candidate. Specific Aim 2 is to determine whether the CBF response to opiate-related cues in methadone-maintained patients is modulated by the fluctuation in methadone plasma levels. Specific Aim 3 is to characterize the effect of the opiate antagonist naltrexone on the CBF response to opiate-related cues in abstinent formerly opiate-dependent patients. The research plan will help determine the role of specific brain structures that mediate cue-induced craving to opiates and potentially to other drugs abuse acting on the mesocorticolimbic reward system. This data would improve our understanding of the mechanisms underlying dependence, treatment resistance and relapse. Furthermore, it may point the way for the development of novel methods for evaluation of the efficacy of pharmacotherapies and individual treatment response prediction in drug dependence. Implementation of this training and research plan will help the candidate to become an independent investigator in the neuropsychiatry of addiction.